Anxiety disorders are among the most common and impairing psychiatric disorders for children, adolescents, and young adults. Nevertheless, the roles that stressors (i.e., extraorganismic challenging circumstances or events) and stress (i.e., the intraorganismic, physiological response to stressors) play in the etiology of anxiety in the early life course are not well understood. A social stressor-based model posits that higher rates of exposure to stressors increase anxiety and a physiological response-based model highlights the distinct physiological profiles of individuals with anxiety. The proposed research joins these explanations to elucidate mechanisms by which stress mediates the impact of stressors on anxiety. Measures of stressors and stress include major environmental risk candidates and key indicators of immuno-competence, inflammatory response, and HPA-axis reactivity. First, are associations among stressors, stress, and anxiety the same within childhood, adolescence, and young adulthood and across these phases of life? Second, building on these analyses, do multiple markers of several key biological stress systems separately and jointly predict anxiety? And third, does the proposed stressor ` stress ` anxiety model differ for different types of anxiety? In answering these fundamental questions, sex differences will be examined. Data come from the nation's largest ongoing, community-representative, prospectively longitudinal, DSM-based, diagnostic study, the Great Smoky Mountains Study (GSMS). The GSMS has assessed stressors, stress, and anxiety on each participant on up to ten occasions spanning ages 9 to 27, providing an unparalleled opportunity to study the etiology of anxiety disorders. The proposed research will reveal the multifaceted pathways that give rise to anxiety;shed new light on the role of biological stress systems in anxiety at different phases of the early life course;use configurations of stressors and stress and consider separate anxiety disorder symptoms to clarify links in the stressor` stress`anxiety chain;and discover sex differences in these mediating chains. Results from the proposed research will have implications for both prevention and intervention research, for basic biosocial research, and, generally speaking, for improving young people's well-being. PUBLIC HEALTH RELEVANCE: The proposed research is the first to comprehensively examine the role of multiple indicators of environmental stressors (i.e., risk factors) and biological stress in the etiology of anxiety in its different manifestations in childhood, adolescence and young adulthood. Understanding how stressors and stress additively and interactively give rise to this common group of disorders is essential to the design of effective prevention and intervention programs for young people at risk for anxiety, and for informing next steps in biosocial research.